Publications
226 results found
Davis BM, Tian K, Pahlitzsch M, et al., 2019, Corrigendum to “Topical Coenzyme Q10 demonstrates mitochondrial-mediated neuroprotection in a rodent model of ocular hypertension” [Mitochondrion 36 (2017) 114–123], Mitochondrion, Vol: 47, Pages: 330-330, ISSN: 1567-7249
Shamsher E, Davis BM, Yap TE, et al., 2019, Neuroprotection in glaucoma: old concepts, new ideas, EXPERT REVIEW OF OPHTHALMOLOGY, Vol: 14, Pages: 101-113, ISSN: 1746-9899
Arranz-Romera A, Davis BM, Bravo-Osuna I, et al., 2019, Simultaneous co-delivery of neuroprotective drugs from multi-loaded PLGA microspheres for the treatment of glaucoma, JOURNAL OF CONTROLLED RELEASE, Vol: 297, Pages: 26-38, ISSN: 0168-3659
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- Citations: 47
D'Esposito F, Miodragovic S, Normando EM, et al., 2018, The 100 000 genomes project and the Western Eye Hospital experience, Publisher: WILEY, Pages: 28-28, ISSN: 1755-375X
Davis B, Guo L, Pahlitzsch M, et al., 2018, RGC cell size and susceptibility to loss in rodent glaucoma models, Publisher: WILEY, Pages: 30-31, ISSN: 1755-375X
Davis B, Pahlitzsch M, Balendra S, et al., 2018, Evaluation of topical curcumin nanoparticles in of rodent glaucoma models, Publisher: WILEY, Pages: 30-30, ISSN: 1755-375X
Guo L, Normando EM, Shah PA, et al., 2018, Oculo-Visual Abnormalities in Parkinson's Disease: Possible Value as Biomarkers, MOVEMENT DISORDERS, Vol: 33, Pages: 1390-1406, ISSN: 0885-3185
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- Citations: 46
Davis BM, Pahlitzsch M, Guo L, et al., 2018, Topical curcumin nanocarriers are neuroprotective in eye disease, Scientific Reports, Vol: 8, ISSN: 2045-2322
Curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5dione) is a polyphenol extracted from turmeric that has long been advocated for the treatment of a variety of conditions including neurodegenerative and inflammatory disorders. Despite this promise, the clinical use of curcumin has been limited by the poor solubility and low bioavailability of this molecule. In this article, we describe a novel nanocarrier formulation comprising Pluronic-F127 stabilised D-α-Tocopherol polyethene glycol 1000 succinate nanoparticles, which were used to successfully solubilize high concentrations (4.3 mg/mL) of curcumin. Characterisation with x-ray diffraction and in vitro release assays localise curcumin to the nanocarrier interior, with each particle measuring <20 nm diameter. Curcumin-loaded nanocarriers (CN) were found to significantly protect against cobalt chloride induced hypoxia and glutamate induced toxicity in vitro, with CN treatment significantly increasing R28 cell viability. Using established glaucoma-related in vivo models of ocular hypertension (OHT) and partial optic nerve transection (pONT), topical application of CN twice-daily for three weeks significantly reduced retinal ganglion cell loss compared to controls. Collectively, these results suggest that our novel topical CN formulation has potential as an effective neuroprotective therapy in glaucoma and other eye diseases with neuronal pathology.
Cordeiro MF, 2018, DARC and Glaucoma, Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404
Normando EM, Blackwell C, Cordeiro MF, 2018, Effect of Topical Trehalose/Hyaluronic Acid on OCT Image Quality in Glaucoma Patients, Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404
Arranz-Romera A, Shamsher E, Esteban-Perez S, et al., 2018, Co-delivery of Dexamethasone-Melatonin-CoQ10 from a microparticulate drug delivery system. Potential usefulness in neuroprotective therapy, Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404
Guo L, Davis B, Ravindran N, et al., 2018, Topical rh-NGF is neuroprotective to retinal ganglion cells by targeting secondary degeneration, Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404
Shamsher E, Davis B, Dev P, et al., 2018, Resveratrol nanoparticles are neuroprotective in vitro suggesting a potential to cure glaucoma and Alzheimer's disease, Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404
Yap TE, Donna P, Almonte MT, et al., 2018, Real-time imaging of retinal ganglion cell apoptosis, Cells, Vol: 7, ISSN: 2073-4409
Monitoring real-time apoptosis in-vivo is an unmet need of neurodegeneration science, both in clinical and research settings. For patients, earlier diagnosis before the onset of symptoms provides a window of time in which to instigate treatment. For researchers, being able to objectively monitor the rates of underlying degenerative processes at a cellular level provides a biomarker with which to test novel therapeutics. The DARC (Detection of Apoptosing Retinal Cells) project has developed a minimally invasive method using fluorescent annexin A5 to detect rates of apoptosis in retinal ganglion cells, the key pathological process in glaucoma. Numerous animal studies have used DARC to show efficacy of novel, pressure-independent treatment strategies in models of glaucoma and other conditions where retinal apoptosis is reported, including Alzheimer’s disease. This may forge exciting new links in the clinical science of treating both cognitive and visual decline. Human trials are now underway, successfully demonstrating the safety and efficacy of the technique to differentiate patients with progressive neurodegeneration from healthy individuals. We review the current perspectives on retinal ganglion cell apoptosis, the way in which this can be imaged, and the exciting advantages that these future methods hold in store.
Yang E, Al-Mugheiry TS, Normando EM, et al., 2018, Real-time imaging of retinal cell apoptosis by confocal scanning laser ophthalmoscopy and its role in glaucoma, Frontiers in Neurology, Vol: 9, ISSN: 1664-2295
Glaucoma is one of the leading causes of irreversible blindness in the world. It is characterized by the progressive loss of retinal ganglion cells (RGCs), mainly through the process of apoptosis. Glaucoma patients often come to clinical attention when irreversible loss of visual function has been already established; therefore, early recognition of RGC apoptosis is inordinately important in disease prevention. The novel technology called Detection of Apoptosing Retinal Cells (DARC) allows real-time in vivo quantification of apoptosing cells through the use of a fluorescent biomarker and a confocal scanning ophthalmoscope. A recent Phase I clinical trial has evaluated the safety of DARC and its ability to detect retinal apoptosis in glaucoma patients and healthy volunteers. Results suggest that DARC may have potential in the early detection of glaucoma, which could help alleviate the medical, social, and economic burden associated with this blinding condition.
Yap TE, Normando EM, Cordeiro MF, 2018, Redefining clinical outcomes and endpoints in glaucoma, Expert Review of Ophthalmology, ISSN: 1746-9899
Yap TE, Davis BM, Guo L, et al., 2018, Annexins in glaucoma, International Journal of Molecular Sciences, Vol: 19, ISSN: 1422-0067
Glaucoma is one of the leading causes of irreversible visual loss, which has been estimated to affect 3.5% of those over 40 years old and projected to affect a total of 112 million people by 2040. Such a dramatic increase in affected patients demonstrates the need for continual improvement in the way we diagnose and treat this condition. Annexin A5 is a 36 kDa protein that is ubiquitously expressed in humans and is studied as an indicator of apoptosis in several fields. This molecule has a high calcium-dependent affinity for phosphatidylserine, a cell membrane phospholipid externalized to the outer cell membrane in early apoptosis. The DARC (Detection of Apoptosing Retinal Cells) project uses fluorescently-labelled annexin A5 to assess glaucomatous degeneration, the inherent process of which is the apoptosis of retinal ganglion cells. Furthermore, this project has conducted investigation of the retinal apoptosis in the neurodegenerative conditions of the eye and brain. In this present study, we summarized the use of annexin A5 as a marker of apoptosis in the eye. We also relayed the progress of the DARC project, developing real-time imaging of retinal ganglion cell apoptosis in vivo from the experimental models of disease and identifying mechanisms underlying neurodegeneration and its treatments, which has been applied to the first human clinical trials. DARC has potential as a biomarker in neurodegeneration, especially in the research of novel treatments, and could be a useful tool for the diagnosis and monitoring of glaucoma.
De Groef L, Cordeiro MF, 2018, Is the Eye an Extension of the Brain in Central Nervous System Disease?, JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS, Vol: 34, Pages: 129-133, ISSN: 1080-7683
Fayers T, Loh GK, Cordeiro MF, et al., 2018, Overprescribing of antibiotics by UK ophthalmologists., Eye, Vol: 32, Pages: 240-242, ISSN: 0950-222X
D'Esposito F, Cennamo G, de Crecchio G, et al., 2018, Multimodal Imaging in Autosomal Dominant Cone-Rod Dystrophy Caused by Novel <i>CRX</i> Variant, OPHTHALMIC RESEARCH, Vol: 60, Pages: 169-175, ISSN: 0030-3747
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- Citations: 3
Sanchez-Lopez E, Antonia Egea M, Davis BM, et al., 2017, Memantine-Loaded PEGylated Biodegradable Nanoparticles for the Treatment of Glaucoma, SMALL, Vol: 14, ISSN: 1613-6810
Glaucoma is a multifactorial neurodegenerative disease associated with retinal ganglion cells (RGC) loss. Increasing reports of similarities in glaucoma and other neurodegenerative conditions have led to speculation that therapies for brain neurodegenerative disorders may also have potential as glaucoma therapies. Memantine is an N-methyl-d-aspartate (NMDA) antagonist approved for Alzheimer's disease treatment. Glutamate-induced excitotoxicity is implicated in glaucoma and NMDA receptor antagonism is advocated as a potential strategy for RGC preservation. This study describes the development of a topical formulation of memantine-loaded PLGA-PEG nanoparticles (MEM-NP) and investigates the efficacy of this formulation using a well-established glaucoma model. MEM-NPs <200 nm in diameter and incorporating 4 mg mL−1 of memantine were prepared with 0.35 mg mL−1 localized to the aqueous interior. In vitro assessment indicated sustained release from MEM-NPs and ex vivo ocular permeation studies demonstrated enhanced delivery. MEM-NPs were additionally found to be well tolerated in vitro (human retinoblastoma cells) and in vivo (Draize test). Finally, when applied topically in a rodent model of ocular hypertension for three weeks, MEM-NP eye drops were found to significantly (p < 0.0001) reduce RGC loss. These results suggest that topical MEM-NP is safe, well tolerated, and, most promisingly, neuroprotective in an experimental glaucoma model.
Davis BM, Brenton J, Davis S, et al., 2017, Assessing anesthetic activity through modulation of the membrane dipole potential, Journal of Lipid Research, Vol: 58, Pages: 1962-1976, ISSN: 0022-2275
There is great individual variation in response to general anesthetics (GAs) leading to difficulties in optimal dosing and sometimes even accidental awareness during general anesthesia (AAGA). AAGA is a rare, but potentially devastating, complication affecting between 0.1% and 2% of patients undergoing surgery. The development of novel personalized screening techniques to accurately predict a patient’s response to GAs and the risk of AAGA remains an unmet clinical need. In the present study, we demonstrate the principle of using a fluorescent reporter of the membrane dipole potential, di-8-ANEPPs, as a novel method to monitor anesthetic activity using a well-described inducer/noninducer pair. The membrane dipole potential has previously been suggested to contribute a novel mechanism of anesthetic action. We show that the fluorescence ratio of di-8-ANEPPs changed in response to physiological concentrations of the anesthetic, 1-chloro-1,2,2-trifluorocyclobutane (F3), but not the structurally similar noninducer, 1,2-dichlorohexafluorocyclobutane (F6), to artificial membranes and in vitro retinal cell systems. Modulation of the membrane dipole provides an explanation to overcome the limitations associated with the alternative membrane-mediated mechanisms of GA action. Furthermore, by combining this technique with noninvasive retinal imaging technologies, we propose that this technique could provide a novel and noninvasive technique to monitor GA susceptibility and identify patients at risk of AAGA.
Davis BM, Tian K, Pahlitzsch M, et al., 2017, Topical coenzyme Q10 demonstrates mitochondrial-mediated neuroprotection in a rodent model of ocular hypertension, Mitochondrion, Vol: 36, Pages: 114-123, ISSN: 1567-7249
Coenzyme Q10 (CoQ10) is a mitochondrial-targeted antioxidant with known neuroprotective activity. Its ocular effects when co-solubilised with α–tocopherol polyethylene glycol succinate (TPGS) were evaluated. In vitro studies confirmed that CoQ10 was significantly protective in different retinal ganglion cell (RGC) models. In vivo studies in Adult Dark Agouti (DA) rats with unilateral surgically-induced ocular hypertension (OHT) treated with either CoQ10/TPGS micelles or TPGS vehicle twice daily for three weeks were performed, following which retinal cell health was assessed in vivo using DARC (Detection of Apoptotic Retinal Cells) and post-mortem with Brn3a histological assessment on whole retinal mounts. CoQ10/TPGS showed a significant neuroprotective effect compared to control with DARC (p < 0.05) and Brn3 (p < 0.01). Topical CoQ10 appears an effective therapy preventing RGC apoptosis and loss in glaucoma-related models.
Bono V, Normando EM, Davis B, et al., 2017, Prospective comparison of global visual field indices and cluster progression in glaucoma and their relationship to structural changes, Publisher: WILEY, ISSN: 1755-375X
Cordeiro MF, 2017, Outcomes and endpoints in glaucoma, Publisher: WILEY, ISSN: 1755-375X
Davis B, Ravindra N, Guo L, et al., 2017, AD in the eye, Publisher: WILEY, ISSN: 1755-375X
Cordeiro MF, Normando EM, Cardoso MJ, et al., 2017, Real-time imaging of single neuronal cell apoptosis in patients with glaucoma, Brain, Vol: 140, Pages: 1757-1767, ISSN: 1460-2156
Retinal cell apoptosis occurs in many ocular neurodegenerative conditions including glaucoma—the major cause of irreversibleblindness worldwide. Using a new imaging technique that we have called DARC (detection of apoptosing retinal cells), which untilnow has only been demonstrated in animal models, we assessed if annexin 5 labelled with fluorescent dye DY-776 (ANX776)could be used safely in humans to identify retinal cell apoptosis. Eight patients with glaucomatous neurodegeneration and evidenceof progressive disease, and eight healthy subjects were randomly assigned to intravenous ANX776 doses of 0.1, 0.2, 0.4 and0.5 mg in an open-label, phase 1 clinical trial. In addition to assessing the safety, tolerability and pharmacokinetics of ANX776, thestudy aimed to explore whether DARC could successfully visualize individual retinal cell apoptosis in vivo in humans, with theDARC count defined as the total number of unique ANX776-labelled spots. DARC enabled retinal cell apoptosis to be identified inthe human retina using ANX776. Single ANX776-labelled cells were visualized in a dose-dependent pattern (P5 0.001) up to 6 hafter injection. The DARC count was significantly higher (2.37-fold, 95% confidence interval: 1.4–4.03, P = 0.003) in glaucomapatients compared to healthy controls, and was significantly (P = 0.045) greater in patients who later showed increasing rates ofdisease progression, based on either optic disc, retinal nerve fibre layer or visual field parameters. Additionally, the DARC countsignificantly correlated with decreased central corneal thickness (Spearman’s R = 0.68, P = 0.006) and increased cup-disc ratios(Spearman’s R = 0.47, P = 0.038) in glaucoma patients and with increased age (Spearman’s R = 0.77, P = 0.001) in healthy controls.Finally, ANX776 was found to be safe and well-tolerated with no serious adverse events, and a short half-life (10–36 min).This proof-of-concept study demonstrates that retinal cell apopt
Normando EM, Bono V, Davis B, et al., 2017, Prospective Comparison of Global and Cluster Visual Field Progression Criteria in Glaucoma and Their Relationship to Structural Changes, Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404
Cordeiro MF, Normando EM, Cardoso MJ, et al., 2017, Phase 1 safety and tolerability assessment of ANX776 in DARC (Detection of Apoptosing Retinal Cells) Technology, Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) - Imaging in the Eye, Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404
Davis BM, Salinas-Navarro M, Cordeiro MF, et al., 2017, Characterizing microglia activation: a spatial statistics approach to maximize information extraction, Scientific Reports, Vol: 7, ISSN: 2045-2322
Microglia play an important role in the pathology of CNS disorders, however, there remains significant uncertainty about the neuroprotective/degenerative role of these cells due to a lack of techniques to adequately assess their complex behaviour in response to injury. Advancing microscopy techniques, transgenic lines and well-characterized molecular markers, have made histological assessment of microglia populations more accessible. However, there is a distinct lack of tools to adequately extract information from these images to fully characterise microglia behaviour. This, combined with growing economic pressures and the ethical need to minimise the use of laboratory animals, led us to develop tools to maximise the amount of information obtained. This study describes a novel approach, combining image analysis with spatial statistical techniques. In addition to monitoring morphological parameters and global changes in microglia density, nearest neighbour distance, and regularity index, we used cluster analyses based on changes in soma size and roundness to yield novel insights into the behaviour of different microglia phenotypes in a murine optic nerve injury model. These methods should be considered a generic tool to quantitatively assess microglia activation, to profile phenotypic changes into microglia subpopulations, and to map spatial distributions in virtually every CNS region and disease state.
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